Cephalosporin derivative

A number of di- and trisubstituted hydrazides of penicillin and cephalosporin derivatives were prepared to study the effect of A-substitution on ease of oxidative cleavage. ... 

Ceftiofur (57) differs from the preceding cephalosporin derivatives in that it ha.s a thioester moiety at C-3. This can be introduced by displacement of the C-3 acetyl group of 7-aminocepha-losporanic acid (40) with hydrogen sulfide and esterification with 2-furylcarboxylic acid to give synthon 5reacted with trimethylsilylated oximinoether derivative 55 (itself obtained from the corresponding acid by reaction with dicyclohexylcarbodiimide and 1-hydroxy-benzotriazole) to produce, after deprotecting, ceftiofur (57) [18]. 

The antibiotic cephalosporin derivative 48 has been reported it was prepared by the coupling reaction of the 1,2,4-thiadiazole acid chloride derivative 46 with the amino cephalosporin derivative 47. Similar cephalosporin derivatives were mentioned in CHEC-II(1996) (Equation 13) <2001JAN364>. 

The 1,2,4-thiadiazole moiety has been incorporated in (3-lactam antibacterials to modulate pharmacokinetic properties and more recently into a cephalosporin. The cephalosporin 129 displays a good balance of serum stability and in vitro activity. The cephalosporin derivative 48 (see Section 5.08.7.4) also shows good pharmacokinetic properties <2001JAN364>. 

Scheme 6.87 Trapping products of cephalosporin derivative 417 with cycloalkenes and 1,2-disubstituted ethylenes.

The efficiency of the [2 + 2]-cycloadditions of 417 was utilized in a strategy for the synthesis of cephalosporin derivatives that carry an acetone or acetic acid ester group in the 3-position (Scheme 6.88) [175]. Liberated in the presence of 2-(trimethylsilyl-oxy)propene, 417 underwent cycloaddition leading to 435, treatment of which with tetrabutylammonium or hydrogen fluoride furnished the A3-cephalosporin 436 admixed with the A2-isomer. This mixture was converted to pure 436 by an oxidation-reduction sequence. In addition to the trimethylsilylenol ether of acetone, the... 

Scheme 6.92 Generation of the cephalosporin-derived cyclic allene 450 from the cephalosporin / -S-oxide triflate 449 and trapping of450 by (Z)-/J-deuterostyrene, furan, 2-acetylfuran, furan-3-carboxylic acid dimethylamide, N-tert-butoxycarbonylpyrrole, pyrrole and N-methylpyrrole.

Scheme 6.93 Generation ofthe cephalosporin-derived cyclic allene 458 from the cephalosporin a-S-oxide triflate 457 and trapping of 458 by furan.

It is reasonable to assume that 5 and styrene generate the diradical 527, which collapses to give 528 at 30 °C under kinetic control. At temperatures of 75 °C and above, the last step is reversible and an equilibrium is established in that 528 and the methylenecyclobutane derivative 529 maintain a ratio of 1 6 [215]. The [2 + 2]-cydoadduct 530 of 5 to phenylacetylene should be formed analogously via a diradical of the type 527 and is closely related in its structure to the cephalosporin derivatives 437 and 438 (R= Ph, Scheme 6.89). In addition to 530, 2-phenylindene was obtained, which has to be considered as the product of the thermal rearrangement of 530 [216]. Akin to such a process, 526 [194] and 529 [215] were converted into indane derivatives on heating. 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

The first example illustrated in Scheme 13 portrays a novel route to the cephalosporin derivative (47) [28, 29] through the intermediacy of the allyl nickel species (46). The second example provides... 

Parish D, Scheinfeld N. (2008) Ceftaroline fosamil, a cephalosporin derivative for the potential treatment of MRSA infection. Curr Opin Invest Drugs 9 201-209. 

New cephalosporin derivatives of the sydnones (1) have been prepared and some sydnones (1) useful as anti-inflammatory drugs have been described. ... 

Early examples of successful, highly diastereoselective alkylations of bicyclic /1-lactams include reactions of the enolates from penicillin and cephalosporin derivatives (e.g., 1 and 4). These enolates have also been used in aldol-type additions, acylations and in the preparation of hetero-substituted penicillins and cephalosporins1. 

A number of interesting studies of lactam hydrolysis have been published. The metal(II)-catalyzed hydrolysis of some penicillin and cephalosporin derivatives displays saturation kinetics.410"412 A 1 1 complex is formed between the metal ion and penicillin which undergoes base hydrolysis up to 10s times faster than the free ligand. The catalytic activity follows the order Cu,>ZnII>NiII = Co11. Coordination of penicillin to copper(II) is believed to occur via the /3-lactam nitrogen and the carboxylate group (121)4l0-4n but other sites have been proposed.413... 

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